From a series of mutagenesis and chimeric investigations the binding site of cholecystokinin (CCK), a peptide hormone and neurotransmitter with a wide spectrum of physiologic actions, has been located to the extracellular domain of the G-protein coupled receptor. To obtain a structural basis for the biomolecular interaction of this hormone and receptor, we have synthesized the 47-amino acid peptide sequence of the N-terminal domain of the receptor (approximately 7 amino acid residues of the first transmembrane helix, to serve as a membrane anchor). Our goal is to structurally characterize this region both in the presence and absence of the natural peptide hormone (truncation studies have indicated that the C-terminal seven residues of the native hormone are sufficient for binding and pharmacological action of CCK). The receptor domain was spectroscopically investigated in the presence of DPC micelles to mimic the membrane environment. The proton spectrum of the receptor domain was very crowded due to an abundance of hydrophobic residues. The presence of the slowly tumbling micelles resulted in a significant broadening of the proton signals which required the use of a high field instrument. The spectra have allowed us to identify a unique fold of the N-terminus that forms the putative binding pocket for the CCK hormone. This fold consisting of an amphipathic beta-sheet, stabilized by a disulfide bridge between two Cys residues, has allowed for atomic insight into the modifications which have been carried out on the G-protein coupled receptor. All of this has been obtained with the structure of the isolated N-terminal domain.